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Stereochemical aspects in the synthesis of novel N -(purin-6-yl)dipeptides as potential antimycobacterial agents
Amino Acids ( IF 3.5 ) Pub Date : 2021-02-18 , DOI: 10.1007/s00726-021-02958-0
Vera V Musiyak 1 , Irina A Nizova 1 , Evgeny N Chulakov 1 , Liliya Sh Sadretdinova 1 , Andrey A Tumashov 1, 2 , Galina L Levit 1 , Victor P Krasnov 1, 2
Affiliation  

The synthesis of purine conjugates with natural amino acids is one of the promising directions in search for novel therapeutic agents, including antimycobacterial agents. The purpose of this study was to synthesize N-(purin-6-yl)dipeptides containing the terminal fragment of (S)-glutamic acid. To obtain the target compounds, two synthetic routes were tested. The first of them is based on coupling of N-(purin-6-yl)-(S)-amino acids to dimethyl (S)-glutamate in the presence of carbodiimide coupling agent followed by the removal of ester groups. However, it turned out that this coupling process was accompanied by racemization of the chiral center of N-(purin-6-yl)-α-amino acids and in all cases led to mixtures of (S,S)- and (R,S)-diastereomers (6:4). Individual (S,S)-diastereomers were obtained using an alternative approach based on the nucleophilic substitution of chlorine in 6-chloropurine or 2-amino-6-chloropurine with corresponding dipeptides as nucleophiles. The enantiomeric purity of the target compounds was confirmed by chiral HPLC. To test the assumption that racemization of the chiral center of N-(purin-6-yl)-α-amino acids occurs with the participation of nitrogen atoms of the imidazole ring via the stage of formation of a chirally labile intermediate, we obtained such structural analogs of N-(purin-6-yl)-(S)-alanine as N-(9-benzylpurin-6-yl)-(S)-alanine and N-(7-deazapurin-6-yl)-(S)-alanine. It was found that coupling of these compounds to dimethyl (S)-glutamate was also accompanied by racemization. This indicates that the imidazole fragment does not play a crucial role in this process. When testing the antimycobacterial activity of some of the obtained compounds, conjugates with moderate activity against the laboratory Mycobacterium tuberculosis H37Rv strain (MIC 3.1–6.25 μg/mL) were identified.



中文翻译:

作为潜在抗分枝杆菌剂的新型 N-(purin-6-yl) 二肽合成中的立体化学方面

嘌呤缀合物与天然氨基酸的合成是寻找新型治疗剂(包括抗分枝杆菌剂)的有希望的方向之一。本研究的目的是合成含有( S )-谷氨酸末端片段的N- (purin-6-yl)二肽。为了获得目标化合物,测试了两种合成路线。其中第一个是基于在碳二亚胺偶联剂存在下将 N-(purin - 6-yl)-( S )-氨基酸与 (S)-谷氨酸二甲酯偶联,然后去除酯基。然而,事实证明,这种偶联过程伴随着N的手性中心的消旋化。-(purin-6-yl)-α-氨基酸,在所有情况下都会产生 ( S,S )- 和 ( R,S )-非对映异构体 (6:4) 的混合物。使用基于氯在 6-氯嘌呤或 2-氨基-6-氯嘌呤中的亲核取代以及相应的二肽作为亲核试剂的替代方法获得单个 ( S,S )-非对映异构体。目标化合物的对映体纯度通过手性 HPLC 确认。为了检验N- (purin-6-yl)-α-氨基酸的手性中心消旋化发生在咪唑环的氮原子参与下通过手性不稳定中间体形成阶段的假设,我们获得了这样的假设N -(purin-6-yl)-( S的结构类似物)-丙氨酸为N- (9-benzylpurin-6-yl)-( S )-丙氨酸和N- (7-deazapurin-6-yl)-( S )-丙氨酸。发现这些化合物与( S )-谷氨酸二甲酯的偶联也伴随着消旋作用。这表明咪唑片段在这个过程中并不起关键作用。在测试一些获得的化合物的抗分枝杆菌活性时,鉴定出对实验室结核分枝杆菌H37Rv 菌株具有中等活性的缀合物 (MIC 3.1–6.25 μg/mL)。

更新日期:2021-02-18
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